PROJECT ABSTRACT HIV infection and heavy alcohol use independently cause inflammation in systemic and neural immune systems through multiple mechanisms. Both HIV and alcohol induce microbial translocation from the gut, systemic immune activation, compromise of the blood-brain barrier, and neuroinflammation. Because 15% of people living with HIV (PLWH) report heavy drinking in the past 30 days, the potential for alcohol to exacerbate immunological and neural dysfunction in HIV is a serious public health concern. Observational research links alcohol use in PLWH to brain abnormalities, cognitive impairment, and increased mortality. However, direct experimental evidence on alcohol-HIV interactions in humans is scarce. COBRE CADRE Research Project 1 (RP1) will investigate whether alcohol use in the context of HIV infection exacerbates inflammatory signaling in the peripheral immune system and central nervous system. Specifically, the study will examine acute effects of moderate alcohol consumption on immune biomarkers, neurometabolites, brain white matter, and cognition in PLWH and healthy controls. We will recruit 48 moderate drinkers who differ on HIV serostatus (24 seropositive individuals, 24 seronegative matched controls) to participate in controlled beverage administration and magnetic resonance imaging (MRI). Participants will be randomized to consume placebo (0 g alcohol/kg body weight) or alcoholic beverage (.60 g/kg; target blood alcohol=.07g/dL). Blood samples will be taken at baseline and for 3 hours after beverage consumption and assayed for plasma biomarkers of microbial translocation, monocyte/macrophage activation, and cytokine response. The plasma ratio of kynurenine to tryptophan will be used as a measure of immune activation relevant to HIV and drinking behavior. Cognition and subjective intoxication will be assessed during the experiment using the standardized measures from the COBRE Clinical Laboratory Core. MRI scans will be collected on the descending limb of alcohol and will focus on correlates of neuroinflammation, including: 1) neurometabolites (choline, Glx, glutathione) in thalamus and frontal white matter, using MR spectroscopy; 2) white matter diffusivity and extracellular free water, using diffusion-weighted imaging (DWI). We hypothesize that alcohol will induce greater pro-inflammatory effects in PLWH, relative to controls, 1) in the peripheral immune system, as reflected in plasma biomarker perturbations and tryptophan degradation; 2) in the brain, as reflected in neurometabolic changes, diffusivity alterations, and increased extracellular water. An exploratory aim tests the prediction that PLWH will show greater subjective intoxication and cognitive impairment in the alcohol condition. The interdisciplinary research team and mentors have experience and expertise in biobehavioral alcohol-HIV research to enable successful completion of this project. RP1 aligns with the overarching COBRE CADRE goal: to identify mechanisms through which substance use exacerbates adverse health outcomes in chronic disease. Results will advance understanding of pathogenic mechanisms of alcohol use and inform efforts to prevent and treat alcohol-related harms, particularly in PLWH.